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Diazepam-D5 preparation method

A technology of diazepam and compounds, which is applied in the field of preparation of deuterated diazepam standard intermediates, can solve the problems of high price, limited wide use, poor stability of deuterated internal standards, etc.

Active Publication Date: 2017-11-21
INST OF FORENSIC SCI OF MIN OF PUBLIC SECURITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The stability of the deuterated internal standard substance is poor. Our country has not yet broken through this technical bottleneck restricting the production of deuterated substances in our country. There is no manufacturer producing the deuterated substances involved in the poisonous substance involved. The use of this product can only rely on imports
For a long time, the deuterated internal standards used in my country have been dependent on imports, and foreign imports are all d 5 - Methanol solution of diazepam instead of solid powder, coupled with its high price, severely limits the wide use of this type of standard product in China

Method used

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  • Diazepam-D5 preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Step (1): 2-acetamide-5-chlorobenzophenone-2',3',4',5',6'-d 5 (Formula II compound) preparation

[0034]

[0035] Put 2.6g of Mg strips in a 250mL three-necked flask, add 50mL of anhydrous THF, then add 30mg of iodine particles, add a THF solution of deuterated bromobenzene dropwise under stirring (8.8g of deuterated bromobenzene is added to 40mL THF), and reflux the reaction After 1 hour, the Grignard reagent was prepared.

[0036] Put 10.0g of raw material 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one (compound of formula I) in a 250mL single-necked bottle, then add 50mL of toluene, and cool down to below 0°C in an ice bath , Add the above-mentioned Grignard reagent dropwise, and the dropping time is greater than 45min. After the addition is complete, stir at 0°C for 30 minutes, then rise to room temperature and stir overnight, then cool the reaction to 0°C, add 100 mL of 6mol / L dilute hydrochloric acid, stir for 30 minutes and then separate the liquids, extract the ...

Embodiment 2

[0052] Embodiment 2 (preparation method of formula V compound)

[0053] Steps (1), (2) are the same as in Example 1.

[0054] Step (3): 2-bromoacetamide-5-chlorobenzophenone-2',3',4',5',6'-d 5 (Formula IV compound) preparation:

[0055]

[0056] Put 7.08g of the compound of formula III in a 250mL round-bottomed flask, add 36mL of toluene to dissolve it, then add 4.74g of pyridine, cool down to 0°C in an ice bath, add dropwise a toluene solution of bromoacetyl bromide (3.9 mL of bromoacetyl bromide is added to 20 mL of chloroform Middle), after TLC monitors that the reaction is completed, add water to quench the reaction, extract the organic phase with toluene (30 mL each time, 3 times in total), combine the organic phases and wash with saturated sodium carbonate, dry and concentrate under reduced pressure to obtain an oily substance, which is The crude product of the compound of formula IV was directly used in the next reaction without purification.

[0057] Step (4): 7-...

Embodiment 3

[0062] The difference between this example and Example 1 lies in step (5): diazepam-D5: 7-chloro-1,3-dihydro-1-methyl-5-(phenyl-d 5 )-2H-1, the preparation of 4-benzodiazepine-2-ketone (formula VI compound):

[0063]

[0064] The compound of formula V (5.5g) was dissolved in DMF (30mL), cooled to -5°C in an ice-salt bath, NaH (0.48g) was added and stirred for 15min. At this time, the system was light yellow and transparent. The DMF solution of methyl iodide (2.8g methyl iodide is dissolved in 25mL DMF) is slowly added dropwise to the reaction system (methyl iodide is dissolved in DMF and slowly added dropwise, in order to avoid producing the by-products of the two methyl groups, separation Purification is difficult and the yield is low), the dropwise addition is completed, and the reaction takes 30 minutes. Then slowly add saturated ammonium chloride to quench the reaction, after extraction with ethyl acetate, combine the organic phases, wash with water three times, after ...

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Abstract

The invention discloses a diazepam-D5 preparation method. According to the method, 6-chlorine-2-methyl-4H-3, 1-benzoxazine-4-ketone (a compound as shown in a formula) serves as a raw material, and the 6-chlorine-2-methyl-4H-3, 1-benzoxazine-4-ketone and deuterated bromobenzene reagents are reacted, hydrolyzed, acylated, cyclized, methylated, separated and purified to obtain diazepam-D5. The preparation method has the advantages of mild reaction condition, simple in operation and the like, and a diazepam-D5 standard product prepared by the method is high in chemical purity and good in quality and stability and can be conveniently used for analyzing preparation of standard products. The preparation method can be used for producing deuterated internal standard substances when the diazepam-D5 is analyzed and detected.

Description

technical field [0001] The invention relates to the field of chemical analysis and detection, in particular to a method for preparing a deuterated diazepam standard product intermediate in the field of forensic science. Background technique [0002] Diazepam is a benzodiazepine central nervous system depressant, which can cause inhibition of different parts of the central nervous system. As the dosage increases, the clinical manifestations can range from mild sedation to hypnosis or even coma. In recent years, criminal cases such as poisoning, suicide, and misuse caused by such drugs have occurred from time to time. This requires the public security judicial appraisal department to test the samples of samples involving such drugs. In order to ensure the preparation and reliability of the detection method, the internal standard is added during the detection, and the corresponding deuterium is the best internal standard. Since its use is non-civilian and has particularity, ou...

Claims

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Application Information

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IPC IPC(8): C07D243/24C07D243/30C07B59/00
CPCC07B59/002C07B2200/05C07D243/24C07D243/30
Inventor 杜鸿雁徐小英魏春明于忠山宋歌
Owner INST OF FORENSIC SCI OF MIN OF PUBLIC SECURITY
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